Transition metal-catalyzed reactions of alkenes are among the most powerful approaches to synthesize functionalized organic compounds for biomedical research. Recent experimental advancements have enabled promising catalytic methods for hydro- and difunctionalization of alkenes, which add a hydrogen and a functional group or two different functional groups across a carbon-carbon double bond in an atom- and step-economical fashion. These approaches can serve as an important new platform for the synthesis of biologically active organic molecules because they can be utilized to construct structurally diverse target molecules using a broad scope of coupling partners. However, it remains a significant challenge to effectively control regio- and stereoselectivity in the reactions with readily available, unactivated alkenes. The current state-of-the-art approach relies on experimental trial-and-error to screen ancillary ligands, additives, and directing groups. Rational catalyst design remains challenging, due to the lack of theoretical understanding about the mechanisms of these multistep catalytic processes and the complex nature of the catalyst-substrate interactions. The overall goal of this proposal is to develop and apply computational tools to address these challenges in the development of transition-metal-catalyzed functionalizations of alkenes. We will perform high-level computational studies to reveal the reaction mechanisms and develop generally applicable models for reactivity and selectivity. These theoretical models aim to provide quantitative and straightforward prediction of the effects of ligands and directing groups. Therefore, they can be effectively applied to various experimental systems to guide future development of new catalytic reactions. During the first three years of my independent career, my group has published 24 manuscripts that focused on three general experimental strategies for alkene functionalization: (1) catalyst-controlled hydrofunctionalization of unactivated alkenes; (2) hydro- and difunctionalization of alkenes utilizing directing groups; and (3) radical-mediated reactions with alkenes. In the next five years, we plan to expand our computational studies to a broader scope of reactions. We will further optimize and validate our theoretical models to enable more robust prediction of reactivity and selectivity. We also intend to establish more collaborations with experimental groups to streamline the use of theoretical insights to guide experimental discovery. The proposed research program is significant and innovative because it aims to address general challenges and provide predictions to a broad range of catalytic reactions, rather than to simply explain existing results for specific experimental systems. Our research is highly unique in collaborating with many prominent experimental groups. These fruitful collaborations allowed us to progress in not only the understanding of many specific examples of alkene functionalization reactions, but also the development of general rules of regio- and stereoselectivity in these processes.